bims-medebr 2022-06-26 papers

bims-medebr

Biomed News

on Metabolism of the developing brain

Issue of 2022–06–26
eightteen papers selected by
Regina F. Fernández, Johns Hopkins University

Abstinence Following Intermittent Methylphenidate Exposure Dose-Dependently Modifies Brain Glucose Metabolism in the Rat Brain.
Delayed Impact of 2-Oxoadipate Dehydrogenase Inhibition on the Rat Brain Metabolism Is Linked to Protein Glutarylation.
One Molecule for Mental Nourishment and More: Glucose Transporter Type 1-Biology and Deficiency Syndrome.
Dietary Long-Chain n-3 Polyunsaturated Fatty Acid Supplementation Alters Electrophysiological Properties in the Nucleus Accumbens and Emotional Behavior in Naïve and Chronically Stressed Mice.
Mitochondrial bioenergetic is impaired in Monocarboxylate transporter 1 deficiency: a new clinical case and review of the literature.
Brain glucose metabolism in schizophrenia: a systematic review and meta-analysis of 18FDG-PET studies in schizophrenia.
Massive Accumulation of Sphingomyelin Affects the Lysosomal and Mitochondria Compartments and Promotes Apoptosis in Niemann-Pick Disease Type A.
Impaired Membrane Lipid Homeostasis in Schizophrenia.
Deletion of the Sodium-Dependent Glutamate Transporter GLT-1 in Maturing Oligodendrocytes Attenuates Myelination of Callosal Axons During a Postnatal Phase of Central Nervous System Development.
Characterization of lipoproteins and associated lipidome in very preterm infants: a pilot study.
Metabolic lactate production coordinates vasculature development and progenitor behavior in the developing mouse neocortex.
Glycogen phosphorylase isoform regulation of glucose and Energy Sensor expression in male versus female rat hypothalamic astrocyte primary cultures.
REM-Sleep Deprivation Induces Mitochondrial Biogenesis in the Rat Hippocampus.
Upregulation of PGC-1α Attenuates Oxygen-Glucose Deprivation-Induced Hippocampal Neuronal Injury.
Effects of sugars, fatty acids and amino acids on cytosolic and mitochondrial hydrogen peroxide release from liver cells.
Mitochondrial SIRT3 Deficiency Results in Neuronal Network Hyperexcitability, Accelerates Age-Related Aβ Pathology, and Renders Neurons Vulnerable to Aβ Toxicity.
An imbalance between RAGE/MR/HMGB1 and ATP1α3 is associated with inflammatory changes in rat brain harboring cerebral aneurysms prone to rupture.
Restricting α-synuclein transport into mitochondria by inhibition of α-synuclein-VDAC complexation as a potential therapeutic target for Parkinson's disease treatment.

Synapse. 2022 Jun 21.

Abstinence Following Intermittent Methylphenidate Exposure Dose-Dependently Modifies Brain Glucose Metabolism in the Rat Brain.

Eliz Arnavut, John Hamilton, Rutao Yao, Munawwar Sajjad, Michael Hadjiargyrou, David Komatsu, Panayotis K Thanos.

  Methylphenidate (MP) is a psychostimulant chronically prescribed for the treatment of attention deficit hyperactivity disorder (ADHD). Additionally, MP users may take breaks from using the medication during "drug holidays" which may include short-term or long-term breaks from medication. The present study utilized fluorodeoxyglucose (FDG) positron emission tomography (PET) to analyze the effects of chronic oral MP use and abstinence on brain glucose metabolism (BGluM) in rats at two different doses: high dose (HD) and low dose (LD). The schedule of treatment was 3 weeks on-treatment and 1 week off-treatment for a period of 13 weeks, followed by an abstinence period of 4 total weeks. Results showed that chronic MP treatment using this schedule did not lead to significant changes in BGluM when comparing the control to HD MP groups. However, significant activation in BGluM was observed after periods of abstinence between control and HD MP rats in the following brain regions: the trigeminal nucleus, reticular nucleus, inferior olive, lemniscus, mesencephalic reticular formation, inferior colliculus, and several areas of the cerebellum. These brain regions and functional brain circuit play a role in facial sensory function, the auditory pathway, organizing connections between the thalamus and cortex, motor learning, auditory function, control over eye movement, auditory information integration, and both motor and cognitive functions. These results, when considered with previous studies, indicate that MP schedule of use may have differing effects on BGluM. BGluM following long-term MP use was dependent on MP dose and schedule of use in rats. This study was conducted in non-ADHD model rats with the aim to establish an understanding of the effects of MP itself, especially given the growing chronic off-label and prescribed use of MP. Further studies are needed for analysis of the drug's effects on an ADHD-model. This article is protected by copyright. All rights reserved.

Keywords:  FDG; Methylphenidate; PET; abstinence; addiction; brain function; functional connectivity; glucose utilization; microPET

DOI:  https://doi.org/10.1002/syn.22243
Front Med (Lausanne). 2022 ;9 896263

Delayed Impact of 2-Oxoadipate Dehydrogenase Inhibition on the Rat Brain Metabolism Is Linked to Protein Glutarylation.

Alexandra I Boyko, Irina S Karlina, Lev G Zavileyskiy, Vasily A Aleshin, Artem V Artiukhov, Thilo Kaehne, Alexander L Ksenofontov, Sergey I Ryabov, Anastasia V Graf, Angela Tramonti, Victoria I Bunik.

   Background: The DHTKD1-encoded 2-oxoadipate dehydrogenase (OADH) oxidizes 2-oxoadipate-a common intermediate of the lysine and tryptophan catabolism. The mostly low and cell-specific flux through these pathways, and similar activities of OADH and ubiquitously expressed 2-oxoglutarate dehydrogenase (OGDH), agree with often asymptomatic phenotypes of heterozygous mutations in the DHTKD1 gene. Nevertheless, OADH/DHTKD1 are linked to impaired insulin sensitivity, cardiovascular disease risks, and Charcot-Marie-Tooth neuropathy. We hypothesize that systemic significance of OADH relies on its generation of glutaryl residues for protein glutarylation. Using pharmacological inhibition of OADH and the animal model of spinal cord injury (SCI), we explore this hypothesis.
Methods: The weight-drop model of SCI, a single intranasal administration of an OADH-directed inhibitor trimethyl adipoyl phosphonate (TMAP), and quantification of the associated metabolic changes in the rat brain employ established methods.
Results: The TMAP-induced metabolic changes in the brain of the control, laminectomized (LE) and SCI rats are long-term and (patho)physiology-dependent. Increased glutarylation of the brain proteins, proportional to OADH expression in the control and LE rats, represents a long-term consequence of the OADH inhibition. The proportionality suggests autoglutarylation of OADH, supported by our mass-spectrometric identification of glutarylated K155 and K818 in recombinant human OADH. In SCI rats, TMAP increases glutarylation of the brain proteins more than OADH expression, inducing a strong perturbation in the brain glutathione metabolism. The redox metabolism is not perturbed by TMAP in LE animals, where the inhibition of OADH increases expression of deglutarylase sirtuin 5. The results reveal the glutarylation-imposed control of the brain glutathione metabolism. Glutarylation of the ODP2 subunit of pyruvate dehydrogenase complex at K451 is detected in the rat brain, linking the OADH function to the brain glucose oxidation essential for the redox state. Short-term inhibition of OADH by TMAP administration manifests in increased levels of tryptophan and decreased levels of sirtuins 5 and 3 in the brain.
Conclusion: Pharmacological inhibition of OADH affects acylation system of the brain, causing long-term, (patho)physiology-dependent changes in the expression of OADH and sirtuin 5, protein glutarylation and glutathione metabolism. The identified glutarylation of ODP2 subunit of pyruvate dehydrogenase complex provides a molecular mechanism of the OADH association with diabetes.

Keywords:  2-oxoadipate dehydrogenase; DHTKD1; citrulline; glutarylation; glutathione; phosphonate analog of 2-oxoadipate; sirtuin 5

DOI:  https://doi.org/10.3389/fmed.2022.896263
Biomedicines. 2022 May 26. pii: 1249. [Epub ahead of print]10(6):

One Molecule for Mental Nourishment and More: Glucose Transporter Type 1-Biology and Deficiency Syndrome.

Romana Vulturar, Adina Chiș, Sebastian Pintilie, Ilinca Maria Farcaș, Alina Botezatu, Cristian Cezar Login, Adela-Viviana Sitar-Taut, Olga Hilda Orasan, Adina Stan, Cecilia Lazea, Camelia Al-Khzouz, Monica Mager, Mihaela Adela Vințan, Simona Manole, Laura Damian.

  Glucose transporter type 1 (Glut1) is the main transporter involved in the cellular uptake of glucose into many tissues, and is highly expressed in the brain and in erythrocytes. Glut1 deficiency syndrome is caused mainly by mutations of the SLC2A1 gene, impairing passive glucose transport across the blood-brain barrier. All age groups, from infants to adults, may be affected, with age-specific symptoms. In its classic form, the syndrome presents as an early-onset drug-resistant metabolic epileptic encephalopathy with a complex movement disorder and developmental delay. In later-onset forms, complex motor disorder predominates, with dystonia, ataxia, chorea or spasticity, often triggered by fasting. Diagnosis is confirmed by hypoglycorrhachia (below 45 mg/dL) with normal blood glucose, 18F-fluorodeoxyglucose positron emission tomography, and genetic analysis showing pathogenic SLC2A1 variants. There are also ongoing positive studies on erythrocytes' Glut1 surface expression using flow cytometry. The standard treatment still consists of ketogenic therapies supplying ketones as alternative brain fuel. Anaplerotic substances may provide alternative energy sources. Understanding the complex interactions of Glut1 with other tissues, its signaling function for brain angiogenesis and gliosis, and the complex regulation of glucose transportation, including compensatory mechanisms in different tissues, will hopefully advance therapy. Ongoing research for future interventions is focusing on small molecules to restore Glut1, metabolic stimulation, and SLC2A1 transfer strategies. Newborn screening, early identification and treatment could minimize the neurodevelopmental disease consequences. Furthermore, understanding Glut1 relative deficiency or inhibition in inflammation, neurodegenerative disorders, and viral infections including COVID-19 and other settings could provide clues for future therapeutic approaches.

Keywords:  Glut1; SLC2A1; cognitive impairment; epilepsy; flow cytometry; glucose uptake; inborn errors of metabolism; inflammation; ketogenic diet; movement disorders

DOI:  https://doi.org/10.3390/biomedicines10061249
Int J Mol Sci. 2022 Jun 14. pii: 6650. [Epub ahead of print]23(12):

Dietary Long-Chain n-3 Polyunsaturated Fatty Acid Supplementation Alters Electrophysiological Properties in the Nucleus Accumbens and Emotional Behavior in Naïve and Chronically Stressed Mice.

Mathieu Di Miceli, Maud Martinat, Moïra Rossitto, Agnès Aubert, Shoug Alashmali, Clémentine Bosch-Bouju, Xavier Fioramonti, Corinne Joffre, Richard P Bazinet, Sophie Layé.

  Long-chain (LC) n-3 polyunsaturated fatty acids (PUFAs) have drawn attention in the field of neuropsychiatric disorders, in particular depression. However, whether dietary supplementation with LC n-3 PUFA protects from the development of mood disorders is still a matter of debate. In the present study, we studied the effect of a two-month exposure to isocaloric diets containing n-3 PUFAs in the form of relatively short-chain (SC) (6% of rapeseed oil, enriched in α-linolenic acid (ALA)) or LC (6% of tuna oil, enriched in eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)) PUFAs on behavior and synaptic plasticity of mice submitted or not to a chronic social defeat stress (CSDS), previously reported to alter emotional and social behavior, as well as synaptic plasticity in the nucleus accumbens (NAc). First, fatty acid content and lipid metabolism gene expression were measured in the NAc of mice fed a SC (control) or LC n-3 (supplemented) PUFA diet. Our results indicate that LC n-3 supplementation significantly increased some n-3 PUFAs, while decreasing some n-6 PUFAs. Then, in another cohort, control and n-3 PUFA-supplemented mice were subjected to CSDS, and social and emotional behaviors were assessed, together with long-term depression plasticity in accumbal medium spiny neurons. Overall, mice fed with n-3 PUFA supplementation displayed an emotional behavior profile and electrophysiological properties of medium spiny neurons which was distinct from the ones displayed by mice fed with the control diet, and this, independently of CSDS. Using the social interaction index to discriminate resilient and susceptible mice in the CSDS groups, n-3 supplementation promoted resiliency. Altogether, our results pinpoint that exposure to a diet rich in LC n-3 PUFA, as compared to a diet rich in SC n-3 PUFA, influences the NAc fatty acid profile. In addition, electrophysiological properties and emotional behavior were altered in LC n-3 PUFA mice, independently of CSDS. Our results bring new insights about the effect of LC n-3 PUFA on emotional behavior and synaptic plasticity.

Keywords:  ALA; DHA; EPA; chronic social defeat stress; emotional behavior; lipid microarray; long-term depression; whole-cell patch-clamp electrophysiology

DOI:  https://doi.org/10.3390/ijms23126650
Orphanet J Rare Dis. 2022 06 21. 17(1): 243

Mitochondrial bioenergetic is impaired in Monocarboxylate transporter 1 deficiency: a new clinical case and review of the literature.

Sinziana Stanescu, Irene Bravo-Alonso, Amaya Belanger-Quintana, Belen Pérez, Montserrat Medina-Diaz, Pedro Ruiz-Sala, Nathaly Paola Flores, Raquel Buenache, Francisco Arrieta, Pilar Rodríguez-Pombo.

   BACKGROUND: Monocarboxylate transporter 1 (MCT1) deficiency has recently been described as a rare cause of recurrent ketosis, the result of impaired ketone utilization in extrahepatic tissues. To date, only six patients with this condition have been identified, and clinical and biochemical details remain incomplete.
RESULTS: The present work reports a patient suffering from severe, recurrent episodes of metabolic acidosis and psychomotor delay, showing a pathogenic loss-of-function variation c.747_750del in homozygosity in SLC16A1 (which codes for MCT1). Persistent ketotic and lactic acidosis was accompanied by an abnormal excretion of organic acids related to redox balance disturbances. Together with an altered bioenergetic profile detected in patient-derived fibroblasts, this suggests possible mitochondrial dysfunction. Brain MRI revealed extensive, diffuse bilateral, symmetric signal alterations for the subcortical white matter and basal ganglia, together with corpus callosum agenesia.
CONCLUSIONS: These findings suggest that the clinical spectrum of MCT1 deficiency not only involves recurrent atacks of ketoacidosis, but may also cause lactic acidosis and neuromotor delay with a distinctive neuroimaging pattern including agenesis of corpus callosum and other brain signal alterations.

Keywords:  Corpus callosum agenesia; Mitochondrial dysfunction; Monocarboxylate transporter 1; Psychomotor delay; Recurrent acidosis; White mater alterations

DOI:  https://doi.org/10.1186/s13023-022-02389-4
Psychol Med. 2022 Jun 22. 1-18

Brain glucose metabolism in schizophrenia: a systematic review and meta-analysis of 18FDG-PET studies in schizophrenia.

Leigh Townsend, Toby Pillinger, Pierluigi Selvaggi, Mattia Veronese, Federico Turkheimer, Oliver Howes.

   BACKGROUND: Impaired brain metabolism may be central to schizophrenia pathophysiology, but the magnitude and consistency of metabolic dysfunction is unknown.
METHODS: We searched MEDLINE, PsychINFO and EMBASE between 01/01/1980 and 13/05/2021 for studies comparing regional brain glucose metabolism using 18FDG-PET, in schizophrenia/first-episode psychosis v. controls. Effect sizes (Hedges g) were pooled using a random-effects model. Primary measures were regional absolute and relative CMRGlu in frontal, temporal, parietal and occipital lobes, basal ganglia and thalamus.
RESULTS: Thirty-six studies (1335 subjects) were included. Frontal absolute glucose metabolism (Hedge's g = -0.74 ± 0.54, p = 0.01; I2 = 67%) and metabolism relative to whole brain (g = -0.44 ± 0.34, p = 0.01; I2 = 55%) were lower in schizophrenia v. controls with moderate heterogeneity. Absolute frontal metabolism was lower in chronic (g = -1.18 ± 0.73) v. first-episode patients (g = -0.09 ± 0.88) and controls. Medicated patients showed frontal hypometabolism relative to controls (-1.04 ± 0.26) while metabolism in drug-free patients did not differ significantly from controls. There were no differences in parietal, temporal or occipital lobe or thalamic metabolism in schizophrenia v. controls. Excluding outliers, absolute basal ganglia metabolism was lower in schizophrenia v. controls (-0.25 ± 0.24, p = 0.049; I2 = 5%). Studies identified reporting voxel-based morphometry measures of absolute 18FDG uptake (eight studies) were also analysed using signed differential mapping analysis, finding lower 18FDG uptake in the left anterior cingulate gyrus (Z = -4.143; p = 0.007) and the left inferior orbital frontal gyrus (Z = -4.239; p = 0.02) in schizophrenia.
CONCLUSIONS: We report evidence for hypometabolism with large effect sizes in the frontal cortex in schizophrenia without consistent evidence for alterations in other brain regions. Our findings support the hypothesis of hypofrontality in schizophrenia.

Keywords:  F-18-deoxyglucose (FDG); glucose; metabolism; positron emission tomography (PET); schizophrenia

DOI:  https://doi.org/10.1017/S003329172200174X
J Mol Neurosci. 2022 Jun 21.

Massive Accumulation of Sphingomyelin Affects the Lysosomal and Mitochondria Compartments and Promotes Apoptosis in Niemann-Pick Disease Type A.

Emma Veronica Carsana, Giulia Lunghi, Simona Prioni, Laura Mauri, Nicoletta Loberto, Alessandro Prinetti, Fabio Andrea Zucca, Rosaria Bassi, Sandro Sonnino, Elena Chiricozzi, Stefano Duga, Letizia Straniero, Rosanna Asselta, Giulia Soldà, Maura Samarani, Massimo Aureli.

  Niemann-Pick type A disease (NPA) is a rare lysosomal storage disorder caused by mutations in the gene coding for the lysosomal enzyme acid sphingomyelinase (ASM). ASM deficiency leads to the consequent accumulation of its uncatabolized substrate, the sphingolipid sphingomyelin (SM), causing severe progressive brain disease. To study the effect of the aberrant lysosomal accumulation of SM on cell homeostasis, we loaded skin fibroblasts derived from a NPA patient with exogenous SM to mimic the levels of accumulation characteristic of the pathological neurons. In SM-loaded NPA fibroblasts, we found the blockage of the autophagy flux and the impairment of the mitochondrial compartment paralleled by the altered transcription of several genes, mainly belonging to the electron transport chain machinery and to the cholesterol biosynthesis pathway. In addition, SM loading induces the nuclear translocation of the transcription factor EB that promotes the lysosomal biogenesis and exocytosis. Interestingly, we obtained similar biochemical findings in the brain of the NPA mouse model lacking ASM (ASMKO mouse) at the neurodegenerative stage. Our work provides a new in vitro model to study NPA etiopathology and suggests the existence of a pathogenic lysosome-plasma membrane axis that with an impairment in the mitochondrial activity is responsible for the cell death.

Keywords:  Lysosomes; Mitochondria; Niemann-Pick; Plasma membrane; SMPD1; Sphingomyelin

DOI:  https://doi.org/10.1007/s12031-022-02036-4
Schizophr Bull. 2022 Jun 25. pii: sbac011. [Epub ahead of print]

Impaired Membrane Lipid Homeostasis in Schizophrenia.

Minghui Li, Yan Gao, Dandan Wang, Xiaowen Hu, Jie Jiang, Ying Qing, Xuhan Yang, Gaoping Cui, Pengkun Wang, Juan Zhang, Liya Sun, Chunling Wan.

   BACKGROUND AND HYPOTHESIS: Multiple lines of clinical, biochemical, and genetic evidence suggest that disturbances of membrane lipids and their metabolism are probably involved in the etiology of schizophrenia (SCZ). Lipids in the membrane are essential to neural development and brain function, however, their role in SCZ remains largely unexplored.
STUDY DESIGN: Here we investigated the lipidome of the erythrocyte membrane of 80 patients with SCZ and 40 healthy controls using ultra-performance liquid chromatography-mass spectrometry. Based on the membrane lipids profiling, we explored the potential mechanism of membrane phospholipids metabolism.
STUDY RESULTS: By comparing 812 quantified lipids, we found that in SCZ, membrane phosphatidylcholines and phosphatidylethanolamines, especially the plasmalogen, were significantly decreased. In addition, the total polyunsaturated fatty acids (PUFAs) in the membrane of SCZ were significantly reduced, resulting in a decrease in membrane fluidity. The accumulation of membrane oxidized lipids and the level of peripheral lipid peroxides increased, suggesting an elevated level of oxidative stress in SCZ. Further study of membrane-phospholipid-remodeling genes showed that activation of PLA2s and LPCATs expression in patients, supporting the imbalance of unsaturated and saturated fatty acyl remodeling in phospholipids of SCZ patients.
CONCLUSIONS: Our results suggest that the mechanism of impaired membrane lipid homeostasis is related to the activated phospholipid remodeling caused by excessive oxidative stress in SCZ. Disordered membrane lipids found in this study may reflect the membrane dysfunction in the central nervous system and impact neurotransmitter transmission in patients with SCZ, providing new evidence for the membrane lipids hypothesis of SCZ.

Keywords:  lipidome; membrane fatty acids; membrane lipids; oxidative stress; phospholipid remodeling; schizophrenia

DOI:  https://doi.org/10.1093/schbul/sbac011
Front Cell Neurosci. 2022 ;16 905299

Deletion of the Sodium-Dependent Glutamate Transporter GLT-1 in Maturing Oligodendrocytes Attenuates Myelination of Callosal Axons During a Postnatal Phase of Central Nervous System Development.

Elizabeth J Thomason, Edna Suárez-Pozos, Fatemah S Afshari, Paul A Rosenberg, Jeffrey L Dupree, Babette Fuss.

  The sodium-dependent glutamate transporter GLT-1 (EAAT2, SLC1A2) has been well-described as an important regulator of extracellular glutamate homeostasis in the central nervous system (CNS), a function that is performed mainly through its presence on astrocytes. There is, however, increasing evidence for the expression of GLT-1 in CNS cells other than astrocytes and in functional roles that are mediated by mechanisms downstream of glutamate uptake. In this context, GLT-1 expression has been reported for both neurons and oligodendrocytes (OLGs), and neuronal presynaptic presence of GLT-1 has been implicated in the regulation of glutamate uptake, gene expression, and mitochondrial function. Much less is currently known about the functional roles of GLT-1 expressed by OLGs. The data presented here provide first evidence that GLT-1 expressed by maturing OLGs contributes to the modulation of developmental myelination in the CNS. More specifically, using inducible and conditional knockout mice in which GLT-1 was deleted in maturing OLGs during a peak period of myelination (between 2 and 4 weeks of age) revealed hypomyelinated characteristics in the corpus callosum of preferentially male mice. These characteristics included reduced percentages of smaller diameter myelinated axons and reduced myelin thickness. Interestingly, this myelination phenotype was not found to be associated with major changes in myelin gene expression. Taken together, the data presented here demonstrate that GLT-1 expressed by maturing OLGs is involved in the modulation of the morphological aspects associated with CNS myelination in at least the corpus callosum and during a developmental window that appears of particular vulnerability in males compared to females.

Keywords:  conditional and inducible knockout; development; glutamate transport; myelination; oligodendrocyte

DOI:  https://doi.org/10.3389/fncel.2022.905299
Pediatr Res. 2022 Jun 23.

Characterization of lipoproteins and associated lipidome in very preterm infants: a pilot study.

Alice Küster, Mikael Croyal, Thomas Moyon, Dominique Darmaun, Khadija Ouguerram, Véronique Ferchaud-Roucher.

BACKGROUND: Preterm birth is associated with higher risks of suboptimal neurodevelopment and cardiometabolic disease later in life. Altered maternal-fetal lipid supply could play a role in such risks. Our hypothesis was that very preterm infants born with very low birth weight (VLBW) have altered lipidome and apolipoprotein profiles, compared with term infants.
METHODS: Seven mothers of VLBW infants born at <32 GA and 8 full-term mother-infant dyads were included. Cholesterol and triglycerides in lipoproteins were determined in maternal plasma and in the two blood vessels of the umbilical cord (vein (UV) and artery (UA)) following FPLC isolation. Apolipoprotein concentrations in lipoproteins and plasma lipidomic analysis were performed by LC-MS/MS.
RESULTS: We found higher cholesterol and VLDL-cholesterol in UV and UA and lower apolipoprotein A-I in HDL2 in UV in preterm neonates. Phosphatidylcholine (PC) containing saturated and monounsaturated fatty acids and specific sphingomyelin species were increased in UV and UA, whereas PC containing docosahexaenoic acid (DHA) was reduced in UV of VLBW neonates.
CONCLUSIONS: Lower DHA-PC suggests a lower DHA bioavailability and may contribute to the impaired neurodevelopment. Altered HDL-2, VLDL, and sphingomyelin profile reflect an atherogenic risk and increased metabolic risk at adulthood in infants born prematurely.
IMPACT: Lower ApoA-I in HDL2, and increased specific sphingomyelin and phosphatidylcholine containing saturated and monounsaturated fatty acid could explain the accumulation of cholesterol in umbilical vein in VLBW preterm neonates. Decreased phosphatidylcholine containing DHA suggest a reduced DHA availability for brain development in VLBW preterm infants. Characterization of alterations in fetal lipid plasma and lipoprotein profiles may help to explain at least in part the causes of the elevated cardiovascular risk known in people born prematurely and may suggest that a targeted nutritional strategy based on the composition of fatty acids carried by phosphatidylcholine may be promising in infants born very early.

DOI: https://doi.org/10.1038/s41390-022-02159-9
Nat Neurosci. 2022 Jun 20.

Metabolic lactate production coordinates vasculature development and progenitor behavior in the developing mouse neocortex.

Xiaoxiang Dong, Qiangqiang Zhang, Xiangyu Yu, Ding Wang, Jiaming Ma, Jian Ma, Song-Hai Shi.

Proper neural progenitor behavior in conjunction with orderly vasculature formation is fundamental to the development of the neocortex. However, the mechanisms coordinating neural progenitor behavior and vessel growth remain largely elusive. Here we show that robust metabolic production of lactate by radial glial progenitors (RGPs) co-regulates vascular development and RGP division behavior in the developing mouse neocortex. RGPs undergo a highly organized lineage progression program to produce diverse neural progeny. Systematic single-cell metabolic state analysis revealed that RGPs and their progeny exhibit distinct metabolic features associated with specific cell types and lineage progression statuses. Symmetrically dividing, proliferative RGPs preferentially express a cohort of genes that support glucose uptake and anaerobic glycolysis. Consequently, they consume glucose in anaerobic metabolism and produce a high level of lactate, which promotes vessel growth. Moreover, lactate production enhances RGP proliferation by maintaining mitochondrial length. Together, these results suggest that specific metabolic states and metabolites coordinately regulate vasculature formation and progenitor behavior in neocortical development.

DOI: https://doi.org/10.1038/s41593-022-01093-7
Mol Cell Endocrinol. 2022 Jun 16. pii: S0303-7207(22)00146-0. [Epub ahead of print] 111698

Glycogen phosphorylase isoform regulation of glucose and Energy Sensor expression in male versus female rat hypothalamic astrocyte primary cultures.

Abdulrahman Alhamyani, Prabhat R Napit, Khaggeswar Bheemanapally, Mostafa M H Ibrahim, Paul W Sylvester, Karen P Briski.

  Astrocyte glycogen constitutes the primary energy fuel reserve in the brain. Current research investigated the novel premise that glycogen turnover governs astrocyte responsiveness to critical metabolic and neurotransmitter (i.e. norepinephrine) regulatory signals in a sex-dimorphic manner. Here, rat hypothalamic astrocyte glycogen phosphorylase (GP) gene expression was silenced by short-interfering RNA (siRNA) to investigate how glycogen metabolism controlled by GP-brain type (GPbb) or GP-muscle type (GPmm) activity affects glucose [glucose transporter-2 (GLUT2)] and energy [5'-AMP-activated protein kinase (AMPK)] biomarker and adrenergic receptor (AR) proteins in each sex. Results show that in the presence of glucose, glycogen turnover is regulated by GPbb in the male or by GPmm in the female, yet in the absence of glucose, glycogen breakdown is controlled by GPbb in each sex. GLUT2 expression is governed by GPmm-mediated glycogen breakdown in glucose-supplied astrocytes of each sex, but glycogenolysis regulates sex-specific glucoprivic GLUT2 up-regulation in the male. GPbb-mediated glycogen disassembly regulates total AMPK and phosphoAMPK levels in male, but not female. During glucoprivation, glycogenolysis up-regulates AMPK content in male astrocytes by GPbb- and GPmm-dependent mechanisms, whereas GPbb-mediated glycogen breakdown inhibits phosphoAMPK expression in female. GPbb and GPmm activity governs alpha2-AR and beta1-AR protein levels in male, but has no effect on these profiles in the female. Outcomes provide novel evidence for sex-specific glycogen regulation of glucose- and energy-sensory protein expression in hypothalamic astrocytes, and identify GP isoforms that mediate such control in each sex. Results also show that glycogen regulation of hypothalamic astrocyte receptivity to norepinephrine is male-specific. Further studies are needed to characterize the molecular mechanisms that underlie sex differences in glycogen control of astrocyte protein expression.

Keywords:  AMPK; Adrenergic receptor; GLUT2; Glycogen; Glycogen phosphorylase; Sex differences

DOI:  https://doi.org/10.1016/j.mce.2022.111698
In Vivo. 2022 Jul-Aug;36(4):36(4): 1726-1733

REM-Sleep Deprivation Induces Mitochondrial Biogenesis in the Rat Hippocampus.

Soon Ae Kim, Sanga Kim, Hae Jeong Park.

   BACKGROUND/AIM: Sleep loss is proposed as a trigger for manic episodes in bipolar disorder in humans. It has been shown that sleep and wakefulness can affect changes in mitochondrial gene expression, oxidative phosphorylation (OXPHOS) activity, and morphology in the brain. In this study, we investigated alterations in mitochondrial bioenergetic function in the brain of rats after 72-h rapid eye movement sleep deprivation (REM-SD).
MATERIALS AND METHODS: Alterations in the mitochondrial DNA (mtDNA) copy number were detected in the prefrontal cortex and hippocampus through amplification of mitochondrially encoded NADH dehydrogenase 1 (mt-Nd1) gene using quantitative real-time polymerase chain reaction. The expression levels of mitochondrial biogenesis-related proteins such as peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A), cytochrome c oxidase subunit 4I1 (COX4I1) and sirtuin 3 (SIRT3) were assessed using western blot analysis and immunohistochemistry.
RESULTS: We found that REM-SD significantly increased the mtDNA copy number in the hippocampus but not in the prefrontal cortex. In addition, REM-SD increased the protein expression of COX4I1 in the hippocampus. Furthermore, we observed manic-like behaviors in rats exposed to 72-h REM-SD. REM-SD increased locomotion in the open-field test and the time spent in open arms in the elevated plus-maze test.
CONCLUSION: REM-SD may induce mitochondrial dysfunction in the brain, which may be involved in the induction of mania.

Keywords:  Mitochondria; hippocampus; manic-like behavior; rapid eye movement sleep deprivation

DOI:  https://doi.org/10.21873/invivo.12885
Neural Plast. 2022 ;2022 9682999

Upregulation of PGC-1α Attenuates Oxygen-Glucose Deprivation-Induced Hippocampal Neuronal Injury.

Bin Han, Hui Zhao, Xingji Gong, Jinping Sun, Song Chi, Tao Liu, Anmu Xie.

Hippocampal neuronal damage likely underlies cognitive impairment in vascular dementia (VaD). PPARγ coactivator-1α (PGC-1α) is a master regulator of mitochondrial biogenesis. However, the role and the precise mechanism of how PGC-1α alleviates hippocampal neuronal injury remain unknown. To address this question, HT-22 cells, an immortalized hippocampal neuron cell line, with or without PGC-1α overexpression were subjected to oxygen-glucose deprivation (OGD), which mimics the circumstance of chronic cerebral hypoperfusion in VaD. After OGD, cell viability was assessed using the MTS assay. The mitochondrial function and reactive oxygen species (ROS) were both detected. ChIP-Seq analysis was employed to discover the underlying molecular mechanism of PGC-1α-mediated neuroprotective effects. Our results showed that mitochondrial membrane potentials were increased and ROS production was decreased in PGC-1α overexpressing cells, which increased cell viability. The further bioinformatics analysis from ChIP-Seq data indicated that PGC-1α may participate in the regulation of apoptosis, autophagy, and mitophagy pathways in HT-22 cells. We found that PGC-1α promoted the LC3-II formation and reduced the neuronal apoptosis determined by TUNEL staining. In addition, PGC-1α upregulated the expressions of mitochondrial antioxidants, including SOD2, Trx2, and Prx3. In summary, our findings indicate that PGC-1α may attenuate OGD-induced hippocampal neuronal damage by regulating multiple mechanisms, like autophagy and mitochondrial function. Thus, PGC-1α may be a potential therapeutic target for hippocampal damage associated with cognitive impairment.

DOI: https://doi.org/10.1155/2022/9682999
Free Radic Biol Med. 2022 Jun 16. pii: S0891-5849(22)00452-X. [Epub ahead of print]188 92-102

Effects of sugars, fatty acids and amino acids on cytosolic and mitochondrial hydrogen peroxide release from liver cells.

Jingqi Fang, Yini Zhang, Akos A Gerencser, Martin D Brand.

  The rates of formation of superoxide and hydrogen peroxide at different electron-donating sites in isolated mitochondria are critically dependent on the substrates that are added, through their effects on the reduction level of each site and the components of the protonmotive force. However, in intact cells the acute effects of added substrates on different sites of cytosolic and mitochondrial hydrogen peroxide production are unclear. Here we tested the effects of substrate addition on cytosolic and mitochondrial hydrogen peroxide release from intact AML12 liver cells. In 30-min starved cells replete with endogenous substrates, addition of glucose, fructose, palmitate, alanine, leucine or glutamine had no effect on the rate or origin of cellular hydrogen peroxide release. However, following 150-min starvation of the cells to deplete endogenous glycogen (and other substrates), cellular hydrogen peroxide production, particularly from NADPH oxidases (NOXs), was decreased, GSH/GSSH ratio increased, and antioxidant gene expression was unchanged. Addition of glucose or glutamine (but not the other substrates) increased hydrogen peroxide release. There were similar relative increases from each of the three major sites of production: mitochondrial sites IQ and IIIQo, and cytosolic NOXs. Glucose supplementation also restored ATP production and mitochondrial NAD reduction level, suggesting that the increased rates of hydrogen peroxide release from the mitochondrial sites were driven by increases in the protonmotive force and the degree of reduction of the electron transport chain. Long-term (24 h) glucose or glutamine deprivation also diminished hydrogen peroxide release rate, ATP production rate and (for glucose deprivation) NAD reduction level. We conclude that the rates of superoxide and hydrogen peroxide production from mitochondrial sites in liver cells are insensitive to extra added substrates when endogenous substrates are not depleted, but these rates are decreased when endogenous substrates are lowered by 150 min of starvation, and can be enhanced by restoring glucose or glutamine supply through improvements in mitochondrial energetic state.

Keywords:  Liver; Mitochondria; NOX; ROS; Site III(Qo); Site IQ

DOI:  https://doi.org/10.1016/j.freeradbiomed.2022.06.225
Neuromolecular Med. 2022 Jun 24.

Mitochondrial SIRT3 Deficiency Results in Neuronal Network Hyperexcitability, Accelerates Age-Related Aβ Pathology, and Renders Neurons Vulnerable to Aβ Toxicity.

Isabella Perone, Nathaniel Ghena, Jing Wang, Chelsea Mackey, Ruiqian Wan, Sulochan Malla, Myriam Gorospe, Aiwu Cheng, Mark P Mattson.

  Aging is the major risk factor for Alzheimer's disease (AD). Mitochondrial dysfunction and neuronal network hyperexcitability are two age-related alterations implicated in AD pathogenesis. We found that levels of the mitochondrial protein deacetylase sirtuin-3 (SIRT3) are significantly reduced, and consequently mitochondria protein acetylation is increased in brain cells during aging. SIRT3-deficient mice exhibit robust mitochondrial protein hyperacetylation and reduced mitochondrial mass during aging. Moreover, SIRT3-deficient mice exhibit epileptiform and burst-firing electroencephalogram activity indicating neuronal network hyperexcitability. Both aging and SIRT3 deficiency result in increased sensitivity to kainic acid-induced seizures. Exposure of cultured cerebral cortical neurons to amyloid β-peptide (Aβ) results in a reduction in SIRT3 levels and SIRT3-deficient neurons exhibit heightened sensitivity to Aβ toxicity. Finally, SIRT3 haploinsufficiency in middle-aged App/Ps1 double mutant transgenic mice results in a significant increase in Aβ load compared with App/Ps1 double mutant mice with normal SIRT3 levels. Collectively, our findings suggest that SIRT3 plays an important role in protecting neurons against Aβ pathology and excitotoxicity.

Keywords:  Amyloid plaques; Electroencephalogram; Epileptic seizures; Excitotoxicity; Protein deacetylase; SOD2

DOI:  https://doi.org/10.1007/s12017-022-08713-2
J Neuroinflammation. 2022 Jun 20. 19(1): 161

An imbalance between RAGE/MR/HMGB1 and ATP1α3 is associated with inflammatory changes in rat brain harboring cerebral aneurysms prone to rupture.

Eiji Shikata, Takeshi Miyamoto, Tadashi Yamaguchi, Izumi Yamaguchi, Hiroshi Kagusa, Daiki Gotoh, Kenji Shimada, Yoshiteru Tada, Kenji Yagi, Keiko T Kitazato, Yasuhisa Kanematsu, Yasushi Takagi.

   BACKGROUND AND PURPOSE: An aneurysmal subarachnoid hemorrhage is a devastating event. To establish an effective therapeutic strategy, its pathogenesis must be clarified, particularly the pathophysiology of brain harboring intracranial aneurysms (IAs). To elucidate the pathology in brain harboring IAs, we examined the significance of the receptor for advanced glycation end-products (RAGE)/mineralocorticoid receptor (MR) pathway and Na+/K+-ATPase (ATP1α3).
METHODS: Ten-week-old female rats were subjected to oophorectomy as well as hypertension and hemodynamic changes to induce IAs, and were fed a high-salt diet. Brain damage in these rats was assessed by inflammatory changes in comparison to sham-operated rats fed a standard diet.
RESULTS: Six weeks after IA induction (n = 30), irregular morphological changes, i.e., an enlarged vessel diameter and vascular wall, were observed in all of the left posterior cerebral arteries (Lt PCAs) prone to rupture. Approximately 20% of rats had ruptured IAs within 6 weeks. In brain harboring unruptured IAs at the PCA, the mRNA levels of RAGE and MR were higher, and that of ATP1α3 was lower than those in the sham-operated rats (p < 0.05, each). Immunohistochemically, elevated expression of RAGE and MR, and decreased expression of ATP1α3 were observed in the brain parenchyma adjacent to the Lt PCA, resulting in increased Iba-1 and S100B expression that reflected the inflammatory changes. There was no difference between the unruptured and ruptured aneurysm rat groups. Treatment with the MR antagonist esaxerenone abrogated these changes, and led to cerebral and vascular normalization and prolonged subarachnoid hemorrhage-free survival (p < 0.05).
CONCLUSIONS: Regulation of the imbalance between the RAGE/MR pathway and ATP1α3 may help attenuate the damage in brain harboring IAs, and further studies are warranted to clarify the significance of the down-regulation of the MR/RAGE pathway and the up-regulation of ATP1α3 for attenuating the pathological changes in brain harboring IAs.

Keywords:  ATP1α3; Brain damage; Cerebral aneurysm; HMGB1; MR; RAGE; SAH

DOI:  https://doi.org/10.1186/s12974-022-02526-7
Cell Mol Life Sci. 2022 Jun 19. 79(7): 368

Restricting α-synuclein transport into mitochondria by inhibition of α-synuclein-VDAC complexation as a potential therapeutic target for Parkinson's disease treatment.

Megha Rajendran, María Queralt-Martín, Philip A Gurnev, William M Rosencrans, Amandine Rovini, Daniel Jacobs, Kaitlin Abrantes, David P Hoogerheide, Sergey M Bezrukov, Tatiana K Rostovtseva.

  Involvement of alpha-synuclein (αSyn) in Parkinson's disease (PD) is complicated and difficult to trace on cellular and molecular levels. Recently, we established that αSyn can regulate mitochondrial function by voltage-activated complexation with the voltage-dependent anion channel (VDAC) on the mitochondrial outer membrane. When complexed with αSyn, the VDAC pore is partially blocked, reducing the transport of ATP/ADP and other metabolites. Further, αSyn can translocate into the mitochondria through VDAC, where it interferes with mitochondrial respiration. Recruitment of αSyn to the VDAC-containing lipid membrane appears to be a crucial prerequisite for both the blockage and translocation processes. Here we report an inhibitory effect of HK2p, a small membrane-binding peptide from the mitochondria-targeting N-terminus of hexokinase 2, on αSyn membrane binding, and hence on αSyn complex formation with VDAC and translocation through it. In electrophysiology experiments, the addition of HK2p at micromolar concentrations to the same side of the membrane as αSyn results in a dramatic reduction of the frequency of blockage events in a concentration-dependent manner, reporting on complexation inhibition. Using two complementary methods of measuring protein-membrane binding, bilayer overtone analysis and fluorescence correlation spectroscopy, we found that HK2p induces detachment of αSyn from lipid membranes. Experiments with HeLa cells using proximity ligation assay confirmed that HK2p impedes αSyn entry into mitochondria. Our results demonstrate that it is possible to regulate αSyn-VDAC complexation by a rationally designed peptide, thus suggesting new avenues in the search for peptide therapeutics to alleviate αSyn mitochondrial toxicity in PD and other synucleinopathies.

Keywords:  Hexokinase 2; Membrane-binding peptide; Proximity ligation assay; Single-channel electrophysiology; Small-peptide inhibitors; Synucleinopathies; Voltage-dependent anion channel

DOI:  https://doi.org/10.1007/s00018-022-04389-w